EP3157934B1 - Low ph synthesis of zinc-lysine complex - Google Patents
Low ph synthesis of zinc-lysine complex Download PDFInfo
- Publication number
- EP3157934B1 EP3157934B1 EP14737463.1A EP14737463A EP3157934B1 EP 3157934 B1 EP3157934 B1 EP 3157934B1 EP 14737463 A EP14737463 A EP 14737463A EP 3157934 B1 EP3157934 B1 EP 3157934B1
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- European Patent Office
- Prior art keywords
- lysine
- zinc
- compound
- zlc
- reaction mixture
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- DDKJKQVNNATMAD-JEDNCBNOSA-N (2s)-2,6-diaminohexanoic acid;zinc Chemical compound [Zn].NCCCC[C@H](N)C(O)=O DDKJKQVNNATMAD-JEDNCBNOSA-N 0.000 title claims description 11
- 230000015572 biosynthetic process Effects 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 239000000203 mixture Substances 0.000 claims description 80
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 73
- 239000004472 Lysine Substances 0.000 claims description 72
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 71
- 238000000034 method Methods 0.000 claims description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 35
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 34
- 239000011541 reaction mixture Substances 0.000 claims description 33
- -1 lysine compound Chemical class 0.000 claims description 30
- 239000011701 zinc Substances 0.000 claims description 25
- 150000003752 zinc compounds Chemical class 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 239000011592 zinc chloride Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 239000011260 aqueous acid Substances 0.000 claims description 9
- 238000002955 isolation Methods 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 229960003646 lysine Drugs 0.000 description 59
- 235000018977 lysine Nutrition 0.000 description 58
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 42
- 239000011787 zinc oxide Substances 0.000 description 33
- 238000009472 formulation Methods 0.000 description 21
- 230000001166 anti-perspirative effect Effects 0.000 description 19
- 239000003213 antiperspirant Substances 0.000 description 19
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 17
- 229910052725 zinc Inorganic materials 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 235000014692 zinc oxide Nutrition 0.000 description 15
- 229910001868 water Inorganic materials 0.000 description 13
- 239000002781 deodorant agent Substances 0.000 description 12
- 210000004243 sweat Anatomy 0.000 description 11
- 241000894006 Bacteria Species 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 239000002243 precursor Substances 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 239000011550 stock solution Substances 0.000 description 7
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 229960005337 lysine hydrochloride Drugs 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 208000026935 allergic disease Diseases 0.000 description 5
- 238000005115 demineralization Methods 0.000 description 5
- 230000002328 demineralizing effect Effects 0.000 description 5
- 208000002925 dental caries Diseases 0.000 description 5
- 201000005581 enamel erosion Diseases 0.000 description 5
- 230000009610 hypersensitivity Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000344 soap Substances 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 235000005074 zinc chloride Nutrition 0.000 description 5
- 208000035985 Body Odor Diseases 0.000 description 4
- 206010040904 Skin odour abnormal Diseases 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000000151 deposition Methods 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000002324 mouth wash Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 229940034610 toothpaste Drugs 0.000 description 3
- 239000000606 toothpaste Substances 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000675 anti-caries Effects 0.000 description 2
- 230000000772 anti-erosive effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 229940051866 mouthwash Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000035900 sweating Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- LCZVSXRMYJUNFX-UHFFFAOYSA-N 2-[2-(2-hydroxypropoxy)propoxy]propan-1-ol Chemical compound CC(O)COC(C)COC(C)CO LCZVSXRMYJUNFX-UHFFFAOYSA-N 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical compound [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002272 anti-calculus Effects 0.000 description 1
- 230000003610 anti-gingivitis Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000002882 anti-plaque Effects 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001680 brushing effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940108925 copper gluconate Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 210000004268 dentin Anatomy 0.000 description 1
- LVYZJEPLMYTTGH-UHFFFAOYSA-H dialuminum chloride pentahydroxide dihydrate Chemical compound [Cl-].[Al+3].[OH-].[OH-].[Al+3].[OH-].[OH-].[OH-].O.O LVYZJEPLMYTTGH-UHFFFAOYSA-H 0.000 description 1
- CKQQMPJQZXIYMJ-UHFFFAOYSA-N dihydrate;dihydrochloride Chemical compound O.O.Cl.Cl CKQQMPJQZXIYMJ-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000021472 generally recognized as safe Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000008833 sun damage Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000000106 sweat gland Anatomy 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229960001939 zinc chloride Drugs 0.000 description 1
- 239000011746 zinc citrate Substances 0.000 description 1
- 235000006076 zinc citrate Nutrition 0.000 description 1
- 229940068475 zinc citrate Drugs 0.000 description 1
- 239000011670 zinc gluconate Substances 0.000 description 1
- 235000011478 zinc gluconate Nutrition 0.000 description 1
- 229960000306 zinc gluconate Drugs 0.000 description 1
- 229960001296 zinc oxide Drugs 0.000 description 1
- UJNPHNKJSKIVTE-SCGRZTRASA-L zinc;(2s)-2-amino-5-(diaminomethylideneamino)pentanoate Chemical compound [Zn+2].[O-]C(=O)[C@@H](N)CCCNC(N)=N.[O-]C(=O)[C@@H](N)CCCNC(N)=N UJNPHNKJSKIVTE-SCGRZTRASA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- ZLC zinc-lysine complex
- PCT/US2012/70489 and PCT/US2012/70498 filed on 19 December 2012 .
- ZLC has the unusual property that under conditions of increasing dilution rather than going into or remaining in solution as the solution becomes more dilute, as would typically be the case for an ionic complex, the ZLC hydrolyzes, to provide a relatively insoluble zinc oxide precipitate.
- the ZLC is useful in antiperspirant products, as it precipitates under sweat conditions that can plug the pores and block sweat release.
- ZLC In the presence of protein, the ZLC will flocculate and plug the sweat glands.
- the zinc oxide precipitate can also inhibit odor-causing bacteria, making ZLC useful as a deodorant.
- ZLC is also useful in skin care products, for example liquid hand soap or body wash, providing controlled deposition of zinc oxide on the skin upon dilution and use, which has an antibacterial effect, and also may help protect against sun damage.
- ZLC can be incorporated in oral care formulations, which upon use and dilution, provide a zinc oxide precipitate that is effective for inhibiting and treating dentinal hypersensitivity, dental caries, and enamel erosion and demineralization.
- the disclosure provides synthetic methods for the production of ZLC.
- the disclosure provides a synthetic method comprising the step of combining a zinc compound selected from ZnO and ZnCl 2 , with a lysine compound selected from lysine and lysine ⁇ HCl, in aqueous and further comprising the step of isolating a zinc-lysine complex of formula [Zn(C 6 H 14 N 2 O 2 ) 2 Cl] + Cl- from the final reaction mixture, preferably wherein the pH of the reaction mixture is 6.3 or less, more preferably 6 or less; and preferably wherein the molar ratio of the zinc compound to the lysine compound is 3:1 to 1:3, e.g., 1:1 to 1:3, e.g., approximately 1:2.
- the molar ratio of the zinc compound to the lysine compound is 2:1 to 1:2.
- the disclosure therefore provides, in a first embodiment, a synthetic method (Method 1) which comprises the step of combining a zinc compound selected from ZnO and ZnCl 2 , with a lysine compound selected from lysine and lysine ⁇ HCl, in aqueous acid, and further comprising the step of isolating a zinc-lysine complex of formula [Zn(C 6 H 14 N 2 O 2 ) 2 Cl]+ Cl- from the final reaction mixture e.g.,
- the disclosure provides a zinc-lysine complex (Complex 2) formed by any of the methods 1-1.18.
- Complex 2 formed by any of the methods 1-1.18.
- the disclosure provides:
- composition 1 for application to the skin, comprising any of Complexes 2-2.6, in combination with a cosmetically acceptable carrier.
- composition 1 a personal care composition for application to the skin, comprising any of Complexes 2-2.6, in combination with a cosmetically acceptable carrier.
- composition 1 provides an antiperspirant or deodorant product comprising any of Complexes 2-2.6, in combination with a cosmetically acceptable carrier, or a liquid soap, for example a hand soap or body wash, comprising any of Complexes 2-2.6, in combination with a cosmetically acceptable carrier.
- the disclosure further provides methods of reducing perspiration comprising applying an antiperspirant effective amount of any of Complexes 2-2.6 to the skin, methods of reducing body odor comprising applying a deodorant-effective amount of any of Complexes 2-2.6 to the skin, and methods of killing bacteria comprising contacting the bacteria with an antibacterially effective amount of any of Complexes 2-2.6.
- the disclosure further provides (i) the use of any of Complexes 2-2.6, to kill bacteria, reduce perspiration, and/or reduce body odor; (ii) the use of any of Complexes 2-2.6, in the manufacture of a composition to kill bacteria, reduce perspiration, and/or reduce body odor; and (iii) any of Complexes 2-2.6, for use in killing bacteria, reducing perspiration, and/or reducing body odor.
- composition 2 e.g., a toothpaste or a mouth rinse, which comprises any of Complexes 2-2.6, e.g., which upon use and dilution, provides a zinc oxide precipitate that is effective for inhibiting and/or treating an indication selected from dentinal hypersensitivity, dental caries, and enamel erosion and demineralization.
- Composition 2 e.g., a toothpaste or a mouth rinse
- any of Complexes 2-2.6 e.g., which upon use and dilution, provides a zinc oxide precipitate that is effective for inhibiting and/or treating an indication selected from dentinal hypersensitivity, dental caries, and enamel erosion and demineralization.
- the disclosure provides methods of inhibiting and/or treating an indication selected from dentinal hypersensitivity, dental caries, and enamel erosion and demineralization, comprising applying Composition 2 or an effective amount of any of Complexes 2-2.6 to the teeth.
- the disclosure further provides (i) the use of any of Complexes 2-2.6, for inhibiting and/or treating an indication selected from dentinal hypersensitivity, dental caries, and enamel erosion and demineralization; (ii) the use of any of Complexes 2-2.6, in the manufacture of a composition for inhibiting and/or treating an indication selected from dentinal hypersensitivity, dental caries, and enamel erosion and demineralization.
- ZLC can be prepared by reacting a zinc compound selected from ZnO and ZnCl 2 , with a lysine compound selected from lysine and lysine ⁇ HCl, in aqueous acid, for example aqueous HCl, preferably wherein the pH of the reaction mixture is 6.3 or less, more preferably 6 or less.
- the methods of the disclosure provide ZLC having improved purity, yield and scalability as compared to prior synthetic procedures wherein the reaction is performed at near-neutral (i.e., above approximately pH 6.3 to about pH 7.4),
- the methods of the disclosure are broadly applicable to preparation of ZLC from several zinc-containing and lysine-containing precursors.
- the zinc-containing compound is ZnO or ZnCl 2
- the lysine-containing compound is lysine or lysine ⁇ HCl.
- the reagents are ZnCl 2 and lysine; or ZnCl 2 and lysine ⁇ HCl; or ZnO and lysine; or ZnO and lysine ⁇ HCl.
- the molar ratio of the zinc-containing compound to the lysine-containing compound is from 1:1 to 1:3; preferably approximately 1:2.
- an aqueous solution of the lysine-containing compound for example lysine ⁇ HCl
- approximately 0.4-1 molar equivalent of acid preferably about 0.5 molar equivalent
- the acid can be provided by, for example, addition of concentrated HCl to the solution of the lysine-containing compound.
- the zinc-containing compound, ZnO or ZnCl 2 is then added to the solution.
- the amount of acid added will be sufficient to ensure that the pH of the reaction mixture is 6.3 or less, preferably 6 or less.
- the reaction can be performed at a variety of temperature conditions. Typically, it is most convenient to perform the reaction at ambient temperature, i.e., approximately 25 °C.
- the reaction is allowed to proceed until complete dissolution of the reactants - i.e.. until the solution is completely clear. This typically takes from a few minutes to several hours, depending upon the specific reaction conditions such as temperature and scale.
- Isolation of the ZLC complex can be accomplished by multiple routes depending upon the desired application. Significantly, no filtering or centrifugation steps are required prior to isolation of the final complex.
- the reaction mixture which is clear, can be stored for more than 3 months at slightly acidic pH (i.e., ⁇ pH 7) without precipitation of ZnO.
- the reaction mixture can be spray dried to a powder for a near 100% yield of all reaction components and easy measurement into a formulation.
- a crystalline salt of ZLC can be isolated upon adjustment of the pH of a concentrated reaction mixture with NaOH to near neutral (pH 6.8), and slow evaporation of the reaction mixture.
- the ZLC may be primarily in the form of a complex, there may be some degree of equilibrium with the zinc compound (zinc oxide or zinc chloride) and the lysine compound (lysine or lysine hydrochloride) precursor materials, so that the proportion of material which is actually in complex compared to the proportion in precursor form may vary depending on the precise conditions of formulation, concentration of materials, pH, presence or absence of water, presence or absence of other charged molecules, and so forth.
- ZLC e.g., any of Complex 2, et seq.
- a suitable base for example a stick, roll-on, spray or aerosol for application to the underarm.
- the ZLC in the presence of charged molecules such as proteins found on the skin, the ZLC has a low zeta potential, and will flocculate, forming plugs which block sweat release. Additional water from sweat can moreover dilute the formulation, causing the complex to decompose, resulting in precipitation of zinc oxide, which can reduce sweat and odor as described above.
- the ZLC is provided in a hand soap or body wash base, the dilution of the ZLC upon washing results in a thin deposition of zinc oxide on the skin, providing an antibacterial effect.
- antiperspirant can refer to any material that can form a plug in a pore to reduce sweating, or antiperspirant refers to those materials classified as antiperspirants by the Food and Drug Administration under 21 CFR part 350.
- Antiperspirants may also be deodorants, particularly in the case of this disclosure, as zinc has antibacterial properties and can reduce odor-causing bacteria on the skin.
- the composition can include the ZLC, e.g., any of Complex 2, et seq. and/or precursors thereof, for example zinc oxide, zinc chloride, lysine and lysine hydrochloride.
- the ZLC is prepared at room temperature by mixing the precursors in an aqueous acidic solution. The in situ formation provides ease of formulation. The precursors can be used instead of first having to form the ZLC.
- the water permitting formation of the ZLC, e.g., any of Complex 2, et seq. from the precursor comes from sweat that comes into contact with the composition after application.
- the amount of ZLC, e.g., any of Complex 2, et seq. in the composition of the disclosure, e.g., Compositions 1, is 0.05 to 10% by weight of the composition.
- precursors, e.g., zinc oxide and lysine hydrochloride are present in amounts such that when combined into the ZLC, e.g., any of Complex 2, et seq., the ZLC, e.g., any of Complex 2, et seq. would be present in an amount of 0.05 to 10 % by weight of the composition. In either of these embodiments, the amount of the ZLC, e.g., any of Complex 2, et seq.
- the amount of the ZLC e.g., any of Complex 2, et seq. is at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 1, at least 2, at least 3, or at least 4 up to 10% by weight of the composition.
- the amount of the ZLC, e.g., any of Complex 2, et seq. is less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, less than 1, less than 0.5 to 0.05 % by weight of the composition.
- the amounts are 0.05 to 5%, 0.05 to 4%, 0.05 to 3%, 0.05 to 2%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2%, 0.5 to 5%, 0.5 to 4%, 0.5 to 3%, or 0.5 to 2% by weight of the composition.
- the total amount of zinc in the composition is 0.05 to 8 % by weight of the composition. In other embodiments, the total amount of zinc is at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5, or at least 1 up to 8% by weight of the composition. In other embodiments, the total amount of zinc in the composition is less than 5, less than 4, less than 3, less than 2, or less than 1 to 0.05% by weight of the composition.
- the composition is anhydrous.
- anhydrous there is less than 5% by weight water, optionally less than 4, less than 3, less than 2, less than 1, less than 0.5, less than 0.1 down to 0% by weight water.
- precursors When provided in an anhydrous composition, precursors, e.g., zinc oxide and lysine hydrochloride, will not significantly react to form the ZLC, e.g., any of Complex 2, et seq..
- the precursors When contacted with a sufficient amount of water, which can be in the form of sweat, the precursors will then react to form the ZLC, e.g., any of Complex 2, et seq..
- the ZLC e.g., any of Complex 2, et seq. when introduced into a sweat duct will flocculate with protein and/or hydrolyze with water and/or sweat to form a precipitate to block the sweat duct.
- the ZLC e.g., any of Complex 2, et seq.
- a zeta potential on the order of +10 to + 60, e.g., between +20 and +50.
- Zeta potential is measured as described below.
- the zeta potential indicates the degree of repulsion between adjacent, similarly charged particles in a dispersion.
- a high zeta potential will tend to confer stability, i.e., the particles will tend to repel one another, and the solution or dispersion will resist aggregation.
- attraction exceeds repulsion and the dispersion will break and flocculate.
- the ZLC e.g., any of Complex 2, et seq.
- the ZLC e.g., any of Complex 2, et seq.
- the ZLC e.g., any of Complex 2, et seq. will behave similarly and flocculate when introduced into a pore and becomes hydrated.
- zinc chloride has a zeta potential of about 0, which is much lower than current antiperspirant salts and the current disclosure.
- the ZLC e.g., any of Complex 2, et seq. can have a conductivity of greater than 8000, optionally greater than 9000, greater than 10,000, or greater than 12,000 ⁇ S/cm.
- the personal care composition can be any type of composition.
- the composition is any composition in which it is desired to include an antibacterial agent for application to the skin.
- examples of such compositions include, but are not limited to, personal care compositions, antiperspirants, deodorants, body washes, shower gels, bar soaps, shampoo, hair conditioners, and cosmetics.
- the carrier represents all other materials in the composition other than the ZLC, e.g., any of Complex 2, et seq. or the zinc oxide and amino acid hydrohalide.
- the amount of carrier is then the amount to reach 100% by adding to the weight of the ZLC, e.g., any of Complex 1, et seq. or the zinc oxide and amino acid hydrohalide.
- the carrier can be any carrier that is used for antiperspirants/deodorants.
- the carrier can be in the form of a stick, a gel, a roll-on, or an aerosol.
- the carrier may include oils and/or silicones and gelling agents.
- An example of a formulation can be found in US2011/0076309A1 .
- Optional ingredients that can be included in an antiperspirant and/or deodorant formulation of the compositions of the disclosure include solvents; water-soluble alcohols such as C 2-8 alcohols including ethanol; glycols including propylene glycol, dipropylene glycol, tripropylene glycol and mixtures thereof; glycerides including mono-, di- and triglycerides; medium to long chain organic acids, alcohols and esters; surfactants including emulsifying and dispersing agents; amino acids including glycine; structurants including thickeners and gelling agents, for example polymers, silicates and silicon dioxide; emollients; fragrances; and colorants including dyes and pigments.
- solvents water-soluble alcohols such as C 2-8 alcohols including ethanol
- glycols including propylene glycol, dipropylene glycol, tripropylene glycol and mixtures thereof
- glycerides including mono-, di- and triglycerides
- an antiperspirant and/or deodorant agent additional to the ZLC e.g., any of Complex 2, et seq.
- an odor reducing agent such as a sulfur precipitating agent, e.g., copper gluconate, zinc gluconate, zinc citrate, etc.
- the antiperspirant compositions can be formulated into topical antiperspirant and/or deodorant formulations suitable for application to skin, illustratively a stick, a gel, a cream, a roll-on, a soft solid, a powder, a liquid, an emulsion, a suspension, a dispersion or a spray.
- the composition can comprise a single phase or can be a multi-phase system, for example a system comprising a polar phase and an oil phase, optionally in the form of a stable emulsion.
- the composition can be liquid, semi-solid or solid.
- the antiperspirant and/or deodorant formulation can be provided in any suitable container such as an aerosol can, tube or container with a porous cap, roll-on container, bottle, container with an open end, etc.
- compositions can be used in a method to reduce sweating by applying the composition to skin.
- the application is to axilla.
- the compositions can be used to kill bacteria by contacting bacteria with the composition.
- the combination of the amino acid or amino acid hydrohalide with the zinc oxide increases the availability of zinc ions, which can then kill bacteria and reduce sweat.
- the disclosure provides (i) a method for controlling perspiration comprising applying to skin an antiperspirant effective amount of a formulation of any embodiment embraced or specifically described herein, e.g., any of Compositions 1 et seq.; and (ii) a method for controlling odor from perspiration comprises applying to skin a deodorant effective amount of a formulation of any embodiment embraced or specifically described herein, e.g., any of Compositions 1 et seq.
- the disclosure provides oral care formulations, e.g., Composition 2, for example a toothpaste, gel, mouthwash, powder, cream, strip, or gum comprising an effective amount of the ZLC of the disclosure, e.g., any of Complex 2, et seq.
- Composition 2 for example a toothpaste, gel, mouthwash, powder, cream, strip, or gum comprising an effective amount of the ZLC of the disclosure, e.g., any of Complex 2, et seq.
- the actives are delivered in the form of a mouthwash
- a person desiring the benefits rinses with the stock solution and natural dilution of the stock solution by saliva will initiate the precipitation of the zinc.
- the person can mix the stock solution with appropriate amount of an aqueous diluent (such as approximately 1 part stock solution and 8 parts water for the zinc-lysine samples), and rinse with the mixture.
- an aqueous diluent such as approximately 1 part stock solution and 8 parts water for the zinc-lysine samples
- the mixture is prepared and immediately transferred into a retaining tray, such as those used in holding whitening gels, and the person can wear the tray for the effective period of time.
- a retaining tray such as those used in holding whitening gels
- the teeth that are in contact with the mixture will be treated.
- the mixture can be in the form of a low-viscosity liquid or a gel.
- the stock solution or a mixture of stock solution with water, is applied to the teeth in a gel formulation, e.g., wherein the gel can stay on the tooth for an extended period of time for effective treatment.
- the ZLC active is provided in a toothpaste. Upon brushing, the active is diluted by saliva and water, leading to precipitation and the formation of deposits and occluding particles.
- the rate of precipitation from the formulation can be modulated by adjusting concentration of the complex in the stock solution, and changing the ratio of the stock to water.
- a more diluted formula leads to faster precipitation and is thus preferred when a fast treatment is desired.
- the benefits of the oral care compositions of the disclosure are numerous. By providing zinc ions and zinc containing compounds that can release zinc ions in oral cavities, the oral care compositions of the disclosure provide antimicrobial, antiplaque, antigingivitis, anti-malodor, anticaries, and anticalculus benefits.
- the occluding particles and the surface deposits are compounds containing zinc (particularly ZnO), as well as other zinc derivatives which can release zinc ions into oral cavities and provide the various benefits as recognized above. Additional benefits include but are not limited to anti-attachment, anti-periodontitis and anti-bone loss, as well as promotion of wound healing.
- a second benefit is the antierosive properties of zinc ions, which form antierosive deposits on tooth surfaces through oxidation and hydrolysis.
- the surface deposits, as well as the occluding particles, can react with and neutralize acids, thus protecting the dental surface from the erosive effects of the acids.
- the more surface depositions/occlusion the treatments lead to the more efficacious the treatments are, and therefore zinc-arginine and zinc-lysine are preferred.
- zinc-arginine and zinc-lysine are preferred.
- beneficial zinc ions and the basic amino acid, lysine are released, providing oral care benefits other than anti-erosion.
- a third benefit is anti-sensitivity benefit as a result of the occlusion. Occlusion of dentin tubules leads to sensitivity relief.
- a fourth benefit is the benefit associated with the lysine.
- the occluding particles and surface deposits contain not only zinc, but also lysine, which provides multiple benefits.
- the basic amino acid leads to higher pH of the plaque and can provide anticaries benefits.
- composition components Unless stated otherwise, all percentages of composition components given in this specification are by weight based on a total composition or formulation weight of 100%.
- the ingredients for use in the compositions and formulations of the present disclosure are preferably cosmetically acceptable ingredients.
- cosmetically acceptable is meant suitable for use in a formulation for topical application to human skin.
- a cosmetically acceptable excipient for example, is an excipient which is suitable for external application in the amounts and concentrations contemplated in the formulations of this disclosure, and includes for example excipients which are "Generally Recognized as Safe” (GRAS) by the United States Food and Drug Administration.
- GRAS Generally Recognized as Safe
- compositions and formulations as provided herein are described and claimed with reference to their ingredients, as is usual in the art. As would be evident to one skilled in the art, the ingredients may in some instances react with one another, so that the true composition of the final formulation may not correspond exactly to the ingredients listed. Thus, it should be understood that the disclosure extends to the product of the combination of the listed ingredients.
- ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
- a zinc compound selected from zinc oxide (ZnO) and zinc chloride (ZnCl 2 ) is reacted with a lysine compound selected from lysine and lysine hydrochloride (lysine ⁇ HCl) in acidic aqueous solution.
- Lysine ⁇ HCl (2 molar equivalents) was dissolved in deionized water with stirring at room temperature. Concentrated hydrochloric acid (HCl, 34-37%) equal to approximately 0.5 molar equivalent was added to the reaction mixture. ZnO (1 molar equivalent) was added to the vessel, and the resultant mixture was stirred until complete dissolution, typically minutes to a few hours. The pH of the reaction is kept at 6 or below.
- the ZLC complex can be kept in solution in the final reaction mixture, which is clear, for more than 3 months at slightly acidic pH (i.e., ⁇ pH 7) without precipitation of ZnO.
- the reaction mixture can be spray dried to a powder, resulting in a near 100% yield of all reaction components; or the reaction mixture can be adjusted to a near-neutral pH (e.g., 6.8), and the crystalline salt of ZLC can be isolated upon slow evaporation of the concentrated ZLC reaction mixture.
- ZLC complex prepared by reaction of lysine ⁇ HCl and ZnO in aqueous acid as described above was compared to ZLC prepared by a previous technique employing near-neutral conditions.
- the two samples are isolated by spray drying and analyzed by nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy.
- NMR spectra of the spray product samples from the present and previous syntheses show identical proton environments under similar pH D 2 O solutions, confirming formation of the same ZLC complex. Comparative IR spectra of the two samples also show similar product formation.
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PCT/US2014/042947 WO2015195117A1 (en) | 2014-06-18 | 2014-06-18 | LOW pH SYNTHESIS OF ZINC-LYSINE COMPLEX |
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BR112016028194A2 (pt) * | 2014-06-18 | 2018-06-26 | Colgate Palmolive Co | síntese de complexo de zinco-lisina a partir de cloreto de zinco |
CA2937490A1 (en) * | 2016-07-29 | 2018-01-29 | Fluid Energy Group Ltd. | Using synthetic acid compositions as alternatives to conventional acids in the oil and gas industry |
US11091502B2 (en) | 2018-12-21 | 2021-08-17 | Colgate-Palmolive Company | Methods for synthesizing zinc-lysine-chloride complex |
US11229591B2 (en) | 2018-12-21 | 2022-01-25 | Colgate-Palmolive Company | Methods for synthesizing zinc-lysine-chloride complex |
US11117906B2 (en) | 2018-12-21 | 2021-09-14 | Colgate-Palmolive Company | Methods for synthesizing zinc-lysine-chloride complex |
WO2020131665A1 (en) | 2018-12-21 | 2020-06-25 | Colgate-Palmolive Company | Zinc-arginine-halide complex |
MX2024000665A (es) * | 2021-07-15 | 2024-01-31 | Procter & Gamble | Composicion antitranspirante. |
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US5061815A (en) * | 1988-07-06 | 1991-10-29 | Zinpro Corporation | Metal lysine complexes and method for producing metal lysine complexes |
US6670494B1 (en) * | 2001-12-17 | 2003-12-30 | J H Brotech, Inc. | Method for preparation of metal organic acid chelates |
CN1362403A (zh) * | 2001-12-25 | 2002-08-07 | 江南大学 | 微波固相合成氨基酸螯合物的制造方法 |
US20040198998A1 (en) * | 2003-04-04 | 2004-10-07 | Marian Holerca | Glycine-free antiperspirant salts with betaine for enhanced cosmetic products |
CN101172956A (zh) * | 2007-10-26 | 2008-05-07 | 白家强 | 单体赖氨酸锌及再转为赖氨酸锌络合物的制备和用途 |
EP2934438B1 (en) | 2012-12-19 | 2017-02-15 | Colgate-Palmolive Company | Zinc amino acid/trimethylglycine halide |
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CN104853720B (zh) | 2012-12-19 | 2017-10-24 | 高露洁-棕榄公司 | 含锌精氨酸/赖氨酸卤化物前体的组合物 |
US9675823B2 (en) | 2012-12-19 | 2017-06-13 | Colgate-Palmolive Company | Two component compositions containing zinc amino acid halide complexes and cysteine |
KR20150095701A (ko) | 2012-12-19 | 2015-08-21 | 콜게이트-파아므올리브캄파니 | 아연 아미노산 할라이드를 포함하는 구강 관리 조성물 |
US9498421B2 (en) | 2012-12-19 | 2016-11-22 | Colgate-Palmolive Company | Two component compositions containing tetrabasic zinc-amino acid halide complexes and cysteine |
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US10494589B2 (en) | 2012-12-19 | 2019-12-03 | Colgate-Palmolive Company | Method for indicating time for washing or indicating delivery of antibacterial agent |
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